U.S. patent application number 11/989143 was filed with the patent office on 2009-09-17 for preparation of mono-/difluorinated hydrocarbon compounds.
This patent application is currently assigned to Rhodia Chimie. Invention is credited to Laurent Saint-Jalmes, Daniel Uguen.
Application Number | 20090234151 11/989143 |
Document ID | / |
Family ID | 36113885 |
Filed Date | 2009-09-17 |
United States Patent
Application |
20090234151 |
Kind Code |
A1 |
Saint-Jalmes; Laurent ; et
al. |
September 17, 2009 |
Preparation of Mono-/Difluorinated Hydrocarbon Compounds
Abstract
Mono- or difluorinated hydrocarbon compounds are prepared from
an alcohol or a carbonylated compound by reacting one of these with
a fluorinating reagent, optionally in the presence of a base, the
fluorinating agent comprising a pyridinium reactant having the
following formula (F), wherein R.sub.0 is an alkyl or cycloalkyl
radical: ##STR00001##
Inventors: |
Saint-Jalmes; Laurent;
(Vourles, FR) ; Uguen; Daniel; (Strasbourg,
FR) |
Correspondence
Address: |
BUCHANAN, INGERSOLL & ROONEY PC
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Assignee: |
Rhodia Chimie
Aubervilliers
FR
CNRS
Paris, Cedex
FR
|
Family ID: |
36113885 |
Appl. No.: |
11/989143 |
Filed: |
July 7, 2006 |
PCT Filed: |
July 7, 2006 |
PCT NO: |
PCT/FR2006/001648 |
371 Date: |
January 16, 2009 |
Current U.S.
Class: |
560/103 ;
570/141 |
Current CPC
Class: |
C07D 213/61 20130101;
C07C 17/16 20130101; C07C 67/307 20130101; C07C 41/22 20130101;
C07C 49/813 20130101; C07C 43/225 20130101; C07C 19/08 20130101;
C07C 49/697 20130101; C07C 17/18 20130101; C07C 45/63 20130101;
C07C 22/08 20130101; C07C 17/16 20130101; C07C 19/08 20130101; C07C
17/18 20130101; C07C 22/08 20130101; C07C 45/63 20130101; C07C
49/813 20130101; C07C 67/307 20130101; C07C 69/65 20130101; C07C
41/22 20130101; C07C 43/225 20130101 |
Class at
Publication: |
560/103 ;
570/141 |
International
Class: |
C07C 67/287 20060101
C07C067/287; C07C 17/16 20060101 C07C017/16; C07C 17/18 20060101
C07C017/18 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 19, 2005 |
FR |
0507651 |
Claims
1.-16. (canceled)
17. A process for the preparation of a monofluoro or difluoro
hydrocarbon-based compound, which comprises reacting an alcohol or
a carbonyl-based compound with a fluorinating reagent, optionally
in the presence of a base, said fluorinating agent comprising a
pyridinium reactant having the following formula: ##STR00021##
wherein: R.sub.0 is an alkyl or cycloalkyl radical.
18. The process as defined by claim 17, said fluorinating reagent
having been prepared in situ by reacting a fluoride source with a
halogenated pyridinium reactant having the following formula:
##STR00022## in which: X is a halogen atom with a higher ranking
and other than fluorine; and R.sub.0 is an alkyl or cycloalkyl
radical.
19. The process as defined by claim 17 or 18, said fluorinating
reagent having the formula (F) or (F.sub.1) being included in a
polycyclic structure, the pyridinium ring being fused to a
saturated, unsaturated or aromatic ring having 5 or 6 carbon
atoms.
20. The process as defined by claim 19, said fluorinating reagent
having the formula (F) or (F.sub.1) in which R.sub.0 is a
C.sub.1-C.sub.4 alkyl radical.
21. The process as defined by claims 17 or 18, said fluorinating
reagent comprising a pyridinium compound in which the quaternized
nitrogen atom is associated with a Y.sup.- counterion selected from
among halides, or sulfonate or carboxylate groups.
22. The process as defined by claim 21, said fluorinating reagent
being selected from the group consisting of:
2-fluoro-N-methylpyridinium tosylate; 2-fluoro-N-methylpyridinium
triflate; 2-fluoro-N-methylpyridinium fluoride;
N-methyl-2-fluoroquinolinium triflate; and
N-methyl-2-fluoroquinolinium fluoride.
23. The process as defined by claim 17, comprising reacting an
alcohol having the general formula (I): R.sub.1--OH (I) wherein:
R.sub.1 is a hydrocarbon-based radical having from 1 to 30 carbon
atoms, which may be a linear or branched, saturated or unsaturated
acyclic aliphatic radical; a saturated, unsaturated or aromatic
cycloaliphatic radical; a linear or branched, saturated or
unsaturated aliphatic radical bearing a cyclic substituent.
24. The process as defined by claim 17, comprising reacting a
carbonyl-based aldehyde or ketone (or diketone) having one of the
general formulae: ##STR00023## wherein: R.sub.3, R.sub.4 and
R.sub.5, which may be identical or different, are each a
hydrocarbon-based radical having from 1 to 40 carbon atoms, which
may be a linear or branched, saturated or unsaturated acyclic
aliphatic radical; a monocyclic or polycyclic, saturated,
unsaturated or aromatic carbocyclic or heterocyclic radical; or a
chain of the aforementioned radicals; with the proviso that R.sub.4
and R.sub.5 may together form a ring member having 5 or 6 atoms;
and the R.sub.4 and R.sub.5 radicals do not contain hydrogen atoms
on the carbon atom in position .alpha. with respect to the carbonyl
group.
25. The process as defined by claim 17, wherein the ratio between
the number of moles of fluorinating reagent and the number of moles
of coreactant ranges from 1 to 3.
26. The process as defined by claim 17, carried out in the presence
of a base, the pKa of which is at least greater than or equal to
4.
27. The process as defined by claim 26, said base comprising a
carbonate, hydrogencarbonate, phosphate, or hydrogenphosphate of an
alkaline metal, or of an alkaline-earth metal, or an organic
base.
28. The process as defined by claim 18, said fluoride source
comprising hydrofluoric acid; a salt; or a quaternary ammonium
fluoride.
29. The process as defined by claim 17, carried out in the presence
of an organic solvent selected from the group consisting of
dimethyl sulfoxide, sulfolane and linear or cyclic carboxamides,
N,N-dimethylacetamide (DMAC), N,N-diethylacetamide,
dimethylformamide (DMF) and diethylformamide; aliphatic and
aromatic nitrites, acetonitrile; halogenated and non-halogenated
aliphatic, cycloaliphatic or aromatic hydrocarbons; and ethers.
30. The process as defined by claim 17, wherein the fluorination
reaction is carried out at a temperature ranging from 0.degree. C.
to 140.degree. C.
31. The process as defined by claim 17, comprising preparing a
monofluoro compound from an alcohol.
32. The process as defined by claim 17, comprising preparing a
gem-difluoro compound from a carbonyl-based compound.
33. The process as defined by claim 25, said ratio ranging from 1.5
to 2.
34. The process as defined by claim 26, said pKa ranging from 7 to
11.
35. The process as defined by claim 30, carried out at a
temperature ranging from 80.degree. to 100.degree..
Description
[0001] The subject of the present invention is a method for
preparing monofluoro or difluoro hydrocarbon-based compounds.
[0002] Fluoro compounds are in general difficult to attain. The
reactivity of the fluorine is such that it is difficult or even
impossible to directly obtain fluoro derivatives.
[0003] One of the most used techniques for manufacturing the fluoro
derivative consists in reacting a halo, generally chloro,
derivative to exchange the halogen with a mineral fluorine, in
general a fluoride of an alkaline metal, usually of high atomic
weight.
[0004] Generally, the fluoride used is potassium fluoride which
constitutes a satisfactory economic compromise.
[0005] Under these conditions, many methods, such as for example
those described in FR 2 353 516 and in the article Chem. Ind.
(1978) --56 have been described and used industrially to obtain
aryl fluorides, aryls onto which electron-withdrawing groups are
grafted.
[0006] Except in the case where the substrate is particularly
suitable for this type of synthesis, this technique has drawbacks,
of which the main ones are those which will be analyzed
hereinbelow.
[0007] The reaction requires reagents like alkaline metal fluorides
such as potassium fluoride, which are made relatively expensive by
the specifications which they must meet in order to be suitable for
this type of synthesis; they must be very pure, dry and in a
suitable physical form.
[0008] Use is also made of reagents such as hydrofluoric acid which
is liquid or diluted by dipolar aprotic solvents. However,
hydrofluoric acid is too powerful a reagent and often results in
undesired polymerization reactions or in tars.
[0009] In this case, and especially in the case where it is desired
to have fluoro derivatives on a carbon of alkyl (including aralkyl)
type that is electron poor due to the presence of
electron-withdrawing type groups, a person skilled in the art finds
himself faced with an alternative of which the terms are hardly
encouraging; either very harsh conditions are chosen and mostly
tars are obtained, or else it takes place under mild reaction
conditions and, in the best of cases, the substrate is found
unchanged. Finally, it should be mentioned that certain authors
have proposed to carry out exchanges using, as a reagent,
hydrofluoric acid salts in the presence of heavy elements in the
form of oxides or fluorides. Among the elements used, mention
should be made of antimony and the heavy metals such as silver or
mercury.
[0010] It is important to find mild fluorination conditions, in
particular that make it possible to convert the carbon-oxygen bonds
to a carbon-fluorine bond.
[0011] Fluorinating reagents that enable this type of reaction to
take place have already been proposed.
[0012] It is known to use an aminosulfur trifluoride (especially
diethylaminosulfur trifluoride (DAST)) as a fluorinating agent (J.
Org. Chem., 40, 3808 (1975); Tetrahedron, 44, 2875 (1988); J.
Fluorine Chem., 43 (3), 405-13, (1989) and 42 (1), 137-43, (1989);
EP 0 905 109). In particular, it makes it possible to convert a
carbonyl group to a difluoromethylene group.
[0013] The disadvantage of DAST is in resulting in foul-smelling
by-products, which are difficult to remove from the reaction
medium.
[0014] H. Hayashi et al. have described
2,2-difluoro-1,3-dimethylimidazoline as a novel fluorinating agent
that allows the conversion of alcohols to monofluoro compounds and
of aldehydes/ketones to gem-difluoro compounds.
[0015] Said reagent does not seem very stable and the yields given
are difficult to attain.
[0016] It was therefore desirable to provide an improved method
making it possible to carry out the fluorination under better
conditions.
[0017] A method has now been found, and it is this which
constitutes the subject of the present invention, for preparing a
monofluoro or difluoro hydrocarbon-based compound from an alcohol
or from a carbonyl-based compound which comprises the reaction of
one of them with a fluorinating reagent, optionally in the presence
of a base, which is characterized in that the fluorinating agent is
a reagent comprising a pyridinium unit corresponding to the
following formula:
##STR00002##
in said formula: [0018] R.sub.0 represents an alkyl or cycloalkyl
group.
[0019] In the present text, the term "alkyl" is understood to mean
a linear or branched hydrocarbon-based chain having from 1 to 6
carbon atoms and preferably from 1 to 4 carbon atoms.
[0020] Examples of preferred alkyl groups are, in particular,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl
groups.
[0021] The term "cycloalkyl" is understood to mean a cyclic or
monocyclic hydrocarbon-based group comprising from 3 to 7 carbon
atoms, preferably 5 or 6 carbon atoms.
[0022] It should be noted that the R.sub.0 group could have another
meaning, for example benzyl, but from an economic viewpoint, there
is no advantage in having a complicated R.sub.0 group. Thus, the
C.sub.1-C.sub.4 alkyl groups, and more particularly the methyl
group, are preferred.
[0023] According to the method of the invention, the fluorination
is carried out using the reagent for fluorinating an alcohol or a
carbonyl-based, aldehyde or ketone compound.
[0024] A first embodiment of the invention consists in preparing a
monofluoro compound from a corresponding hydroxylated compound
(alcohol).
[0025] Another variant of the invention consists in preparing a
gem-difluoro compound from a carbonyl-based compound.
[0026] A fluorinating reagent comprising the unit corresponding to
the formula (F) is involved in the method of the invention.
[0027] One preferred reagent is to make use of 1-alkyl- or
1-cycloalkyl-2-fluoropyridinium, but the invention also envisages
the case where said unit is included in a polycyclic structure such
that, for example, the pyridinium ring is fused to a saturated,
unsaturated or aromatic ring having 5 or 6 carbon atoms.
[0028] As more specific examples, mention may be made of 1-alkyl-
or 1-cycloalkyl-2-fluoroquinolinium.
[0029] The invention does not exclude the presence of one or more
(to a maximum of 4) substituents on a or the rings of the reagent,
in particular on the pyridinium ring.
[0030] As examples, given by way of illustration, mention may
especially be made of alkyl or alkoxy groups having from 1 to 4
carbon atoms, a halogen atom (F, Cl, Br, I) or an
electron-withdrawing group for example a nitro group or a
carboxylate of an alkyl having from 1 to 4 atoms.
[0031] According to another embodiment of the invention, the fluoro
reagent may be prepared in situ by using, combined with a fluoride
source, a halogenated reagent comprising a pyridinium unit
corresponding to the following formula:
##STR00003##
in said formula: [0032] X represents a halogen atom with a higher
ranking than fluorine, preferably chlorine, bromine, or iodine; and
[0033] R.sub.0 represents an alkyl or cycloalkyl group.
[0034] It should be noted that in the pyridinium unit of formula
(F) or (F.sub.1), the nitrogen atom is quaternized. The counterion
with which it is associated and which is symbolized by Y.sup.-
results from the method of preparing said unit. It is preferably a
halide, or a sulfonate or carboxylate group.
[0035] As examples of halides, mention may be made of fluoride,
chloride, bromide or iodide.
[0036] As for the sulfonate group, it may be represented by the
formula R.sub.aSO.sub.3.sup.- in which R.sub.a is a
hydrocarbon-based group.
[0037] In said formula, R.sub.a is a hydrocarbon-based group of any
nature. However, it is advantageous from an economic viewpoint that
R.sub.a is of a simple nature, and more particularly represents a
linear or branched alkyl group having from 1 to 4 carbon atoms,
preferably a methyl or ethyl group, but it may also represent for
example a phenyl or tolyl group or a trifluoromethyl group. Among
the R.sub.aSO.sub.3.sup.- groups, the preferred group is a triflate
group which corresponds to an R.sub.a group representing a
trifluoromethyl group.
[0038] Y.sup.- may also be a carboxylate group which may be
represented by the formula R.sub.bCO.sub.2.sup.- in which R.sub.b
is a hydrocarbon-based group.
[0039] As for the sulfonate group, the nature of R.sub.b is not
very important but it is economically desirable that R.sub.b be an
alkyl group having from 1 to 4 carbon atoms, preferably a methyl
group.
[0040] As fluorinating reagents preferably used in the method of
the invention, mention may especially be made of: [0041]
2-fluoro-N-methylpyridinium tosylate; [0042]
2-fluoro-N-methylpyridinium triflate; [0043]
2-fluoro-N-methylpyridinium fluoride; [0044]
N-methyl-2-fluoroquinolinium triflate; and [0045]
N-methyl-2-fluoroquinolinium fluoride.
[0046] The amount of fluorinating reagent used is expressed
relative to the amount of substrate, alcohol or carbonyl-based
compound. It is preferably at least equal to the stoichiometric
amount. It is such that the ratio between the number of moles of
fluorinating reagent and the number of moles of substrate usually
varies between 1 and 3 and is preferably between 1.5 and 2.
[0047] According to the method of the invention, an alcohol or a
carbonyl-based compound is reacted with the fluorinating reagent of
the invention, in the presence of a base and in an organic
medium.
Alcohol
[0048] As for the alcohol, it more particularly corresponds to the
general formula (I):
R.sub.1--OH (I)
in said formula (I): [0049] R.sub.1 represents a hydrocarbon-based
group having from 1 to 30 carbon atoms, which may be a linear or
branched, saturated or unsaturated acyclic aliphatic group; a
saturated, unsaturated or aromatic cycloaliphatic group; a linear
or branched, saturated or unsaturated aliphatic group bearing a
cyclic substituent.
[0050] The alcohol which is involved in the method of the invention
corresponds to the formula (I) in which R.sub.1 represents a linear
or branched, saturated or unsaturated acyclic aliphatic group.
[0051] More specifically, R.sub.1 represents a linear or branched
alkyl, alkenyl, alkadienyl or alkynyl group preferably having from
1 to 30 carbon atoms.
[0052] The hydrocarbon-based chain may possibly be: [0053]
interrupted by one of the following groups: [0054] --O--, --CO--,
--COO--, --OCOO--, --S--, --SO.sub.2--, --NR.sub.2--,
--CO--NR.sub.2--, [0055] in these formulae, R.sub.2 represents
hydrogen or an alkyl group, preferably a methyl or ethyl group;
and/or [0056] a bearer of one of the following substituents: [0057]
--OH, --OCOO--, --COOR.sub.2, --CHO, --NO.sub.2, --X, --CF.sub.3,
[0058] in these formulae, R.sub.2 having the meaning given
previously.
[0059] The linear or branched, saturated or unsaturated, acyclic
aliphatic remainder may possibly bear a cyclic substituent. The
term "ring" is understood to mean a saturated, unsaturated or
aromatic carbocyclic or heterocyclic ring.
[0060] The acyclic aliphatic remainder may be linked to the ring by
a valence bond or by one of the following groups: [0061] --O--,
--CO--, --COO--, --OCOO--, --S--, --SO.sub.2--, --NR.sub.2--,
--CO--NR.sub.2--, [0062] in these formulae, R.sub.2 having the
meaning given previously.
[0063] As examples of cyclic substituents, it is possible to
envisage cycloaliphatic, aromatic or heterocyclic substituents,
especially cycloaliphatic substituents comprising 6 carbon atoms in
the ring or benzene substituents.
[0064] In the general formula (I) of the alcohols, R.sub.1 may also
represent a carbocyclic group that is saturated or that comprises 1
or 2 unsaturations in the ring, generally having from 3 to 7 carbon
atoms, preferably 6 carbon atoms in the ring.
[0065] As preferred examples of R.sub.1 groups, mention may be made
of cyclohexyl or cyclohexene/cyclohexenyl groups.
[0066] It should be noted that when the R.sub.1 group represents a
ring, the invention also includes the case where the ring may bear
one or more substituents insofar as they do not interfere with the
method of the invention. Mention may especially be made of alkyl or
alkoxy groups having from 1 to 4 carbon atoms.
[0067] The method is easily carried out with most alcohols.
[0068] As more particular examples of alcohols, mention may be made
of: [0069] lower aliphatic alcohols having from 1 to 5 carbon
atoms, such as for example, methanol, ethanol, trifluoroethanol,
propanol, isopropyl alcohol, butanol, isobutyl alcohol, sec-butyl
alcohol, tert-butyl alcohol, pentanol, isopentyl alcohol,
sec-pentyl alcohol and tert-pentyl alcohol, ethylene glycol
monoethyl ether, methyl lactate, isobutyl lactate, methyl D-lactate
and isobutyl D-lactate; [0070] higher aliphatic alcohols having at
least 6 and up to around 20 carbon atoms, such as for example,
hexanol, heptanol, isoheptyl alcohol, octanol, isooctyl alcohol,
2-ethylhexanol, sec-octyl alcohol, tert-octyl alcohol, nonanol,
isononyl alcohol, decanol, dodecanol, tetradecanol, octadecanol,
hexadecanol, oleyl alcohol, eicosyl alcohol, and diethylene glycol
monoethyl ether; [0071] cycloaliphatic alcohols having from 3 to
about 20 carbon atoms, such as for example, cyclopropanol,
cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol,
cyclooctanol, cyclododecanol, tripropylcyclohexanol,
methylcyclohexanol and methylcycloheptanol, cyclopentenol,
cyclohexenol; and [0072] an aliphatic alcohol bearing an aromatic
group having from 7 to around 20 carbon atoms, such as for example,
benzyl alcohol, phenethyl alcohol, phenylpropyl alcohol,
phenyloctadecyl alcohol and naphthyldecyl alcohol.
[0073] It is also possible to use polyols, especially
polyoxyethylene glycols, such as for example, ethylene glycol,
diethylene glycol, triethylene glycol, propylene glycol and
glycerol.
[0074] Among the aforementioned alcohols, the following are
preferably used in the method of the invention: aliphatic or
cycloaliphatic alcohols, preferably primary or secondary aliphatic
alcohols having 1 to 4 carbon atoms.
[0075] One variant of the method of the invention consists in using
a terpene alcohol and more particularly a terpene alcohol of
formula (Ia):
T-OH (Ia)
in said formula (Ia): [0076] T represents the remainder of a
terpene alcohol having a number of carbon atoms which is a multiple
of 5.
[0077] In the description which follows of the present invention,
the term "terpene" is understood to mean the oligomers derived from
isoprene.
[0078] More specifically, the alcohol used corresponds to the
general formula (Ia) in which the remainder T represents a
hydrocarbon-based group having from 5 to 40 carbon atoms and more
particularly a linear or branched, saturated or unsaturated
aliphatic group; a monocyclic or polycyclic, saturated, unsaturated
or aromatic, cycloaliphatic group comprising rings having from 3 to
8 carbon atoms.
[0079] It will be specified, without however limiting the scope of
the invention, that the remainder T represents the remainder of:
[0080] a linear or branched, saturated or unsaturated, aliphatic
terpene alcohol; [0081] a saturated or unsaturated, or aromatic,
monocyclic, cycloaliphatic terpene alcohol; [0082] a polycyclic,
cycloaliphatic terpene alcohol comprising at least two saturated
and/or unsaturated carbocycles.
[0083] Regarding the remainder T of a linear or branched, saturated
or unsaturated, aliphatic terpene alcohol, the number of carbon
atoms varies between 5 and 40 carbon atoms. As more specific
examples of remainder T, mention may be made of the groups
comprising 8 carbon atoms, that are saturated or that have a double
bond, and that bear two methyl groups, preferably in position 3 and
7.
[0084] When this is a monocyclic compound, the number of carbon
atoms in the ring may vary widely from 3 to 8 carbon atoms but it
is preferably 5 or 6 carbon atoms.
[0085] The carbocycle may be saturated or comprising 1 or 2
unsaturations in the ring, preferably 1 to 2 double bonds which are
usually in position .alpha. of the oxygen atom.
[0086] In the case of an aromatic terpene alcohol, the aromatic
ring is generally a benzene ring.
[0087] The compound may also be polycyclic, preferably bicyclic,
which means that at least two rings have two carbon atoms in
common. In the case of polycyclic compounds, the number of carbon
atoms in each ring varies between 3 and 6: the total number of
carbon atoms being preferably equal to 7.
[0088] Given below are examples of a commonly encountered bicyclic
structure:
##STR00004##
[0089] In the case of a ring, the presence of substituents is not
excluded insofar as they are compatible with the envisaged
application. The substituents usually borne by the carbocycle are
one or more alkyl groups, preferably three methyl groups, a
methylene group (corresponding to an exocyclic bond), an alkenyl
group, preferably an isopropenyl group.
[0090] As examples of terpene alcohols capable of being used,
mention may be made of: [0091] saturated or unsaturated aliphatic
terpene alcohols such as: [0092] 3,7-dimethyloctanol; [0093]
hydroxycitronellol; [0094] 1-hydroxy-3,7-dimethyl-7-octene; [0095]
nerol; [0096] geraniol; [0097] linalool; and [0098] citronellol;
[0099] aromatic cycloaliphatic terpene alcohols such as: [0100]
thymol; [0101] saturated or unsaturated, monocyclic or polycyclic,
cycloaliphatic terpene alcohols such as: [0102] chrysanthemyl
alcohol; [0103] 1-hydroxyethyl-2,2,3-trimethylcyclopentane; [0104]
.beta.-terpineol; [0105] 1-methyl-3-hydroxy-4-isopropylcyclohexene;
[0106] .alpha.-terpineol; [0107] terpinene-4-ol; [0108]
1,3,5-trimethyl-4-hydroxymethylcyclohexene; and [0109]
isoborneol.
[0110] Among the aforementioned alcohols, the preferred alcohols
are the following: [0111] chrysanthemyl alcohol; [0112]
3,7-dimethyloctanol; [0113] geraniol; [0114] linalool; [0115]
citronellol; [0116] hydroxycitronellol; [0117] nerol; [0118]
thymol; [0119] menthol; and [0120] isoborneol.
Carbonyl-Based Compound
[0121] Involved in the method of the invention, as substrates, may
be an aldehyde or ketone (or diketone) corresponding to one of the
general formulae:
##STR00005##
in said formulae: [0122] R.sub.3, R.sub.4 and R.sub.5, being
identical or different, represent a hydrocarbon-based group
comprising from 1 to 40 carbon atoms which may be a linear or
branched, saturated or unsaturated acyclic aliphatic group; a
monocyclic or polycyclic, saturated, unsaturated or aromatic
carbocyclic or heterocyclic group; or a chaining of the
aforementioned groups; [0123] the R.sub.4 and R.sub.5 groups may be
linked together to form a ring comprising 5 or 6 atoms; and [0124]
the R.sub.4 and R.sub.5 groups do not comprise hydrogen atoms on
the carbon atom in position .alpha. with respect to the carbonyl
group.
[0125] The invention may use symmetrical ketones or diketones if,
in the formulae (III) or (IV), R.sub.4 is identical to R.sub.5 and
dissymmetrical ketones or diketones if R.sub.4 is different to
R.sub.5.
[0126] More specifically in the formulae (II) to (IV), R.sub.3,
R.sub.4 and R.sub.5 represent a hydrocarbon-based group having from
1 to 20 carbon atoms which may be a linear or branched, saturated
or unsaturated acyclic aliphatic group; a monocyclic or polycyclic,
saturated, unsaturated or aromatic carbocyclic or heterocyclic
group; or a linear or branched, saturated or unsaturated, aliphatic
group bearing a cyclic substituent.
[0127] R.sub.3, R.sub.4 and R.sub.5 preferably represent a linear
or branched, saturated acyclic aliphatic group preferably having
from 1 to 12 carbon atoms, and even more preferably from 1 to 4
carbon atoms.
[0128] The invention does not exclude the presence of an
unsaturation on the hydrocarbon-based chain such as one or more
double bonds which may be conjugated or unconjugated, or a triple
bond.
[0129] The hydrocarbon-based chain may optionally be interrupted by
a heteroatom (for example, oxygen or sulfur) or by a functional
group insofar as this does not react and in particular mention may
be made of a group such as --CO-- especially.
[0130] The hydrocarbon-based chain may optionally bear one or more
substituents (for example, halogen, ester) insofar as they do not
interfere with the ketonization reaction.
[0131] The linear or branched, saturated or unsaturated, acyclic
aliphatic group may optionally bear a cyclic substituent. The term
"ring" is understood to mean a saturated, unsaturated or aromatic
carbocyclic or heterocyclic ring.
[0132] The acyclic aliphatic group may be connected to the ring by
a valence bond, a hetero atom or a functional group such as an oxy,
carbonyl, carboxy, sulfonyl, etc. group.
[0133] As examples of cyclic substituents, it is possible to
envisage cycloaliphatic, aromatic or heterocyclic substituents,
especially cycloaliphatic substituents comprising 6 carbon atoms in
the ring or benzene substituents, these cyclic substituents
themselves optionally bearing a substituent of any type insofar as
they do not disturb the reactions taking place in the method of the
invention. Mention may be made, in particular, of alkyl or alkoxy
groups having from 1 to 4 carbon atoms.
[0134] Among the aliphatic groups bearing a cyclic substituent,
cycloalkylalkyl groups, for example cyclohexylalkyl groups or
aralkyl groups having from 7 to 12 carbon atoms, especially benzyl
or phenylethyl groups, are more particularly targeted.
[0135] In the formulae (III) or (IV), R.sub.3, R.sub.4 and R.sub.5
may also represent a saturated or unsaturated carbocyclic group
preferably having 5 or 6 carbon atoms in the ring; a saturated or
unsaturated heterocyclic group especially comprising 5 or 6 atoms
in the ring, including 1 or 2 heteroatoms such as nitrogen, sulfur
and oxygen atoms; a monocyclic, aromatic, carbocyclic or
heterocyclic group, preferably a phenyl, pyridyl, pyrazolyl or
imidazolyl group or a fused or unfused polycyclic group, preferably
a naphthyl group.
[0136] Since one of the R.sub.3, R.sub.4 and R.sub.5 groups
comprises a ring, this may also be substituted. The nature of the
substituent may be any insofar as it does not interfere with the
main reaction. The number of substituents is generally at most 4
per ring but usually equal to 1 or 2.
[0137] Among all the meanings given previously, R.sub.3 preferably
represents a linear or branched alkyl group having from 1 to 12
carbon atoms, preferably from 1 to 6 carbon atoms or a phenyl
group.
[0138] As mentioned previously, the R.sub.4 and R.sub.5 groups do
not comprise hydrogen atoms on the carbon atom in position .alpha.
with respect to the carbonyl group.
[0139] Thus, the carbon atoms in position .alpha. with respect to
the carbonyl group are tertiary carbon atoms. An example of a
tertiary carbon atom may be represented by the formula
(R.sub.6)(R.sub.7)(R.sub.8)C--in which R.sub.6, R.sub.7 and R.sub.8
represent, in particular, a halogen atom, preferably a fluorine
atom; a linear or branched alkyl group having from 1 to 6 carbon
atoms; the R.sub.6, R.sub.7 and R.sub.8 groups, which may also form
a ring, for example a phenyl group optionally included in a
polycyclic structure such as, for example, of naphthalenic
type.
[0140] In the formulae (III) and (IV), the R.sub.4 and R.sub.5
groups may be bonded together to form a ring comprising 5 or 6
atoms: as the carbon atoms located at position .alpha. on both
sides of the carbonyl group [formula (III)] or of the carbonyl
groups [formula (IV)] are tertiary this means that they are either
substituted (as mentioned above) or are included in an unsaturated
or aromatic ring having 5 or 6 atoms, preferably a benzene
ring.
[0141] As specific examples of ketones which may be used in the
method of the invention, mention may more particularly be made of:
[0142] benzophenone; [0143] 2-methylbenzophenone; [0144]
2,4-dimethylbenzophenone; [0145] 4,4'-dimethylbenzophenone; [0146]
2,2'-dimethylbenzophenone; [0147] 4,4'-dimethoxybenzophenone;
[0148] 4-benzoylbiphenyl; [0149] fluorenone; and [0150]
phenanthrene-9,10-dione.
[0151] Given below are examples of alcohols and of carbonyl-based
compounds used in the method of the invention: 1-decanol,
1-decanol, isopropyl mandelate, anisaldehyde, terephthaldehyde and
phenanthrene-9,10-dione.
Base
[0152] A base is optionally involved in the method of the
invention, the role of which is to trap the leaving group which is
an acid halide.
[0153] The characteristic of the base is that it has a pKa at least
greater than or equal to 4, preferably between 5 and 14, and more
preferably between 7 and 11.
[0154] The pKa is defined as the ionic dissociation constant of the
acid/base pair, when water is used as a solvent.
[0155] For the choice of a base having a pKa as defined by the
invention, reference may be made, amongst others, to the Handbook
of Chemistry and Physics, 66th edition, p. D-161 and D-162.
[0156] Another requirement that governs the choice of the base is
that it be non-nucleophilic, that is to say that it is not
substituted for the substrate in the reaction.
[0157] Another characteristic of the base is that it is preferred
that it be soluble in an organic medium.
[0158] Among the bases suitable for the method of the invention,
mention may be made, amongst others, of mineral bases such as
carbonates, hydrogencarbonates, phosphates, or hydrogenphosphates
of alkaline metals, preferably of sodium, potassium or cesium or of
alkaline-earth metals, preferably of calcium, barium or
magnesium.
[0159] Also suitable are organic bases such as tertiary amines and
mention may more particularly be made of triethylamine,
tri-n-propylamine, tri-n-butylamine, methyldibutylamine,
methyldicyclohexylamine, ethyldiisopropylamine,
N,N-diethylcyclohexylamine, pyridine, dimethylamino-4-pyridine,
N-methylpiperidine, N-ethylpiperidine, N-n-butylpiperidine,
1,2-dimethylpiperidine, N-methylpyrrolidine,
1,2-dimethylpyrrolidine.
[0160] Among the bases, preferably triethylamine is chosen.
[0161] The amount of base used expressed relative to the pyridinium
salt is at least equal to the stoichiometric amount. More
preferably it is such that the ratio between the number of moles of
pyridinium salt and the number of moles of base preferably varies
between 1 and 3 and even more preferably between 1.5 and 2.
Fluoride Source
[0162] The fluoride is introduced into the medium in the form of
salt(s).
[0163] Mention may be made, by way of example, of hydrofluoric
acid; the salts such as for example potassium fluoride or ammonium
fluoride.
[0164] It is also possible to make use of quaternary ammonium
fluorides, preferably tetraalkylammonium fluorides, and more
particularly tetrapropylammonium and tetrabutylammonium fluorides;
tetraalkylammonium hydrogendifluorides, preferably ammonium
hydrogendifluoride.
[0165] Preferably, tetrabutylammonium fluoride (TBAT) is
chosen.
[0166] The amount of fluoride source used expressed relative to the
oxygenated substrate is at least equal to the stoichiometric
amount. More preferably, it is such that the ratio between the
number of moles of fluoride and the number of moles of substrate
(alcohol or ketone) preferably varies between 1 and 3, and even
more preferably between 1.5 and 2.
Organic Solvent
[0167] The reaction is generally carried out in the presence of a
reaction solvent.
[0168] A solvent is chosen which is inert under the reaction
conditions.
[0169] As more specific examples of solvents that are suitable for
the present invention, mention may preferably be made of the polar
aprotic solvents such as dimethyl sulfoxide, sulfolane or linear or
cyclic carboxamides, such as N,N-dimethylacetamide (DMAC),
N,N-diethylacetamide, dimethylformamide (DMF) or diethylformamide;
aliphatic or aromatic nitriles, preferably acetonitrile,
propionitrile, butanenitrile, isobutanenitrile, pentanenitrile,
2-methylglutaronitrile, adiponitrile, benzonitrile, tolunitrile,
malonitrile, 1,4-benzonitrile.
[0170] As other examples of less polar organic solvents that are
suitable for the invention, mention may especially be made of
halogenated or nonhalogenated aliphatic, cycloaliphatic or aromatic
hydrocarbons; or ethers.
[0171] It is also possible to make use of aliphatic and
cycloaliphatic hydrocarbons, more particularly paraffins such as
especially hexane, heptane, octane, isooctane, nonane, decane,
undecane, tetradecane, petroleum ether and cyclohexane; aromatic
hydrocarbons such as especially benzene, toluene, xylenes,
ethylbenzene, diethylbenzenes, trimethylbenzenes, cumene,
pseudocumene, and petroleum cuts composed of a mixture of
alkylbenzenes, especially Solvesso.RTM. type cuts.
[0172] It is also possible to use aliphatic or aromatic halogenated
hydrocarbons, mention may more particularly be made of the
perchlorinated hydrocarbons such as, in particular,
tetrachloroethylene and hexachloroethane; partially chlorinated
hydrocarbons such as dichloromethane, chloroform,
1,2-dichloroethane, 1,1,1-trichloroethane,
1,1,2,2-tetrachloroethane, pentachloroethane, trichloroethylene,
1-chlorobutane, 1,2-dichlorobutane; monochlorobenzene,
1,2-dichloro-benzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene,
1,2,4-trichlorobenzene or mixtures of various chlorobenzenes.
[0173] Preferably, dichloromethane or chloroform are chosen.
[0174] As examples of solvents, mention may be made of aliphatic,
cycloaliphatic or aromatic ethers and, more particularly, diethyl
ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl
tert-butyl ether, dipentyl ether, diisopentyl ether, ethylene
glycol dimethyl ether (or 1,2-dimethoxyethane), diethylene glycol
dimethyl ether (or 1,5-dimethoxy-3-oxapentane), dioxane or
tetrahydrofuran.
[0175] It is also possible to use a mixture of organic
solvents.
[0176] The amount of organic solvent used is preferably chosen such
that the weight concentration of the starting substrate in the
solvent is between 5 and 40%, preferably between 10 and 20%.
[0177] The reaction is generally carried out at a temperature
between 0.degree. C. and 140.degree. C., preferably between
80.degree. C. and 100.degree. C.
[0178] The fluorination reaction is generally carried out under
atmospheric pressure but preferably under a controlled atmosphere
of inert gases. It is possible to establish an atmosphere of rare
gases, preferably argon but it is more economical to use nitrogen.
A pressure slightly greater than or less than atmospheric pressure
may be suitable.
[0179] From a practical point of view, the reaction is simple to
implement.
[0180] The order the reagents are used in is not critical. One
preferred variant consists in charging the substrate, the solvent
and the fluorinating agent and then the base and heating to the
desired temperature.
[0181] The reaction time is very variable. It may be from 1 to 24
hours and is preferably between 8 and 15 hours.
[0182] At the end of the reaction, the fluoro product is recovered
by implementing the usual techniques of a person skilled in the
art.
[0183] Generally, water is added to dissolve the salts in the
aqueous phase and a non-miscible solvent, for example
dichloroethane, toluene or monochlorobenzene is added in order to
recover the fluoro compound obtained in the organic phase.
[0184] The aqueous and organic phases are then separated.
[0185] The fluoro compound is recovered according to conventional
separation methods, for example by distillation or by
crystallization in a suitable solvent, especially an ether such as
isopropyl ether or else an alcohol such as methanol, ethanol or
isopropanol.
[0186] The fluorinating reagents according to the invention
comprising the units (F) or (F.sub.1) may be prepared
conventionally.
[0187] Reference may especially be made to the works by P. H. Gross
et al. [J. Org. Chem. (1991), 56, 509-513) for preparing
2-fluoro-N-methylpyridinium tosylate and Marvell et al., J. Am.
Chem. Soc. (1929), 51, 3640 for preparing
2-chloro-N-methylpyridinium tosylate.
[0188] One route for attaining said reagents consists in carrying
out a reaction for alkylating a 2-halopyridine which may be
represented by the following formula:
##STR00006##
in said formula, X.sub.1 represents a fluorine, chlorine, bromine
or iodine atom.
[0189] As alkylating agents, use may be made of alkyl halides,
preferably having a low C.sub.1-C.sub.4 carbon number and
preferably methyl iodide or bromide.
[0190] It is also possible to use a sulfonic acid or carboxylic
acid halide that may be represented by the following formulae:
R.sub.aSO.sub.3X.sub.2 (VI) and
R.sub.bCO.sub.2X.sub.2 (VII)
in which R.sub.a and R.sub.b have the meaning given previously and
X.sub.2 represents a halogen atom, chlorine, bromine or iodine.
[0191] The 2-halopyridine is reacted with an alkylating agent as
mentioned above.
[0192] Generally, the alkylating agent is in a slight excess, the
molar ratio between the alkylating agent and the 2-halopyridine
advantageously varies between 1.1 and 1.2.
[0193] The temperature of the alkylation reaction is generally
between 0.degree. C. and 80.degree. C., preferably between
20.degree. C. and 50.degree. C.
[0194] The reaction is carried out in the presence of an organic
solvent that is inert under the reaction conditions.
[0195] As examples of solvents, mention may especially be made of
halogenated or nonhalogenated aliphatic or aromatic hydrocarbons or
else of nitrites. Reference may be made to the lists given
previously in the present text.
[0196] Dichloromethane, chlorobenzene and toluene are
preferred.
[0197] The pyridinium salt formed precipitates in the reaction
medium.
[0198] The precipitate is recovered according to conventional
solid/liquid separation techniques, preferably by filtration.
[0199] The precipitate may be washed, preferably using the organic
solvent used during the reaction, then the solvent is removed by
evaporation.
[0200] It is then used in the method of the invention.
[0201] According to one variant of the invention, it is possible to
prepare the 1-alkyl- or 1-cycloalkyl-2-fluoropyridinium from a
reagent comprising another halogen, for example a 1-alkyl- or
1-cycloalkyl-2-chloropyridinium by carrying out the exchange of
chlorine with a fluorine atom, by using a fluoride of an alkaline
metal, preferably of sodium or potassium.
[0202] The starting reagent is suspended in an organic solvent such
as mentioned previously, for example acetonitrile, then the
alkaline metal fluoride is added in powder form in an amount
ranging from the stoichiometric amount up to an amount in excess,
for example, of 20%.
[0203] The alkaline metal chloride formed is separated according to
conventional solid/liquid separation techniques, preferably by
filtration.
[0204] The fluoro reagent is then recovered.
[0205] Exemplary embodiments of the invention are given below by
way of illustration and nonlimitingly.
[0206] The yield defined in the examples corresponds to the ratio
between the number of moles of product formed and the number of
moles of substrate used.
[0207] The examples A to K relate to the preparation of the
fluorinating reagent and the following examples, to their use for
preparing monofluoro compounds (Examples 1 to 5) or difluoro or
polyfluoro compounds (Examples 6 to 8).
EXAMPLES
Example A
Preparation of 2-chloro-N-methylpyridinium tosylate
##STR00007##
[0209] In a 25 ml round-bottomed flask topped with a condenser,
2-chloropyridine (2.3 g, 20.6 mmol) and methyl tosylate (3.83 g,
20.6 mmol) were heated at 80-85.degree. C. for one hour.
[0210] Hot toluene (15 ml) was then added before the mixture was
cooled and crystallized.
[0211] The whole mixture was left stirring for 10 minutes and the
mixture was left to return to room temperature.
[0212] The crystallized bottom phase was recovered.
[0213] The product was in the form of a white solid and was
obtained with a yield of 88% (5.4 g).
[0214] The NMR characteristics were the following:
[0215] .sup.1H NMR (300 MHz, CDCl.sub.3): 2.26 (s, 3H); 4.35 (s,
3H); 7.04 (d, J=8 Hz, 2H); 7.56 (d, J=8 Hz, 2H); 7.85-7.91 (m, 2H);
8.38-8.44 (m, 1H); 9.34 (d, J=5.3 Hz, 1H).
[0216] .sup.13C NMR (75 MHz, CDCl.sub.3): [0217] Primaries: 21.3;
47.8. [0218] Secondaries: - [0219] Tertiaries: 125.7; 126.7 (2C);
128.8 (2C); 129.5; 149.6; 154.5. [0220] Quaternaries: 140.1; 143.4;
147.4.
Example B
Preparation of 2-chloro-N-methylpyridinium triflate
##STR00008##
[0222] In a 25 ml round-bottomed flask, 2-chloropyridine (2 g, 20.6
mmol) was diluted in 15 ml of toluene.
[0223] Using a syringe, methyl triflate (2.33 ml, 20.6 mmol) was
added to this solution.
[0224] The mixture was left stirring magnetically at room
temperature for one hour.
[0225] The precipitate was then filtered over a Buchner funnel.
[0226] The traces of solvent were removed via evaporation under a
reduced pressure of around 20 mmHg.
[0227] The product was in the form of a white solid and was
obtained with a yield of 99%.
[0228] The NMR characteristics were the following:
[0229] .sup.1H NMR (300 MHz, DMSO): 4.33 (s, 3H); 8.08 (ddd, J=7.6
Hz, J=6.2 Hz, J=1, 3 Hz, 1H); 8.37 (dd, J=8.3 Hz, J=1.3 Hz, 1H),
8.58 (ddd, J=8 Hz, J=8 Hz, J=1.6 Hz, 1H); 9.16 (dd, J=6.2 Hz, J=1.6
Hz, 1H).
[0230] .sup.13C NMR (75 MHz, DMSO): [0231] Primaries: 47.3. [0232]
Secondaries: - [0233] Tertiaries: 126.1; 129.4; 147.0; 148.2.
[0234] Quaternaries: 170.6 (q, J=322.2 Hz); 121.1 (q, J=322
Hz).
Example C
Preparation of 2-fluoro-N-methylpyridinium tosylate from
2-fluoropyridine
[0235] In a 25 ml round-bottomed flask topped with a condenser,
2-fluoropyridine (2 g, 20.6 mmol) was diluted in 15 ml of
toluene.
[0236] Using a syringe, methyl tosylate (3.83 g, 20.6 mmol) was
added to this solution.
[0237] The mixture was refluxed with magnetic stirring
overnight.
[0238] During the reaction a second yellow phase appeared which
crystallized at room temperature.
[0239] The precipitate was then filtered over a Buchner funnel.
[0240] The traces of solvent were removed via evaporation under a
reduced pressure of around 20 mmHg.
[0241] The product was in the form of a yellow solid and was
obtained with a yield of 89% (5.16 g).
Example D
Preparation of 2-fluoro-N-methylpyridinium tosylate from
2-chloro-N-methylpyridinium tosylate
[0242] In a 50 ml round-bottomed flask topped with a condenser,
2-chloro-Nmethylpyridinium tosylate (4.77 g, 15.9 mmol) was
dissolved in 20 ml of acetonitrile.
[0243] Added to this solution was "spray dried" potassium fluoride
(1.02 g, 17.5 mmol, 1.1 eq.) previously dried under a reduced
pressure of around 20 mmHg at high temperature.
[0244] The whole mixture was refluxed for one hour.
[0245] The potassium chloride was filtered over a Buchner funnel
after cooling the solution.
[0246] The filtrate was concentrated under a reduced pressure of
around 20 mmHg, then was redissolved in 100 ml of
dichloromethane.
[0247] The mixture was filtered again which made it possible to
remove the excess potassium fluoride.
[0248] The filtrate was concentrated again under a reduced pressure
of around 20 mmHg.
[0249] The solid recovered was then finely ground in methyl t-butyl
ether for one hour then the mixture was filtered.
[0250] The product was in the form of a yellow solid and was
obtained with a yield of 90%.
[0251] The NMR characteristics were the following:
[0252] .sup.1H NMR (300 MHz, CDCl.sub.3): 2.31 (s, 3H); 4.29 (d,
J=3.8 Hz, 3H); 7.10 (d, J=8 Hz, 2H); 7.58 (d, J=8 Hz, 2H); 7.62
(dd, J=8.4 Hz, J=4.2 Hz, 1H); 7.79 (m, 1H); 8.52 (m, 1H); 9.07 (m,
1H).
[0253] .sup.13C NMR (75 MHz, CDCl.sub.3) [0254] Primaries: 21.3;
42.0 (d, J=5.3 Hz). [0255] Secondaries: - [0256] Tertiaries: 114.0
(d, J=19.9 Hz); 124.3 (d, J=3.8 Hz); 125.8 (2C); 128.8 (2C); 145.8
(d, J=7.7 Hz); 150.9 (d, J=11 Hz). [0257] Quaternaries: 139.9;
142.6; 158.6 (d, J=278.3 Hz).
Example E
Preparation of 2-fluoro-N-methylpyridinium triflate from
2-fluoropyridine
##STR00009##
[0259] In a 25 ml round-bottomed flask, 2-fluoropyridine (2 g, 20.6
mmol) was diluted in 15 ml of toluene.
[0260] Using a syringe, methyl triflate (2.33 ml, 20.6 mmol) was
added to this solution.
[0261] After a few minutes, a white precipitate was formed.
[0262] The mixture was left stirring magnetically at room
temperature for one hour.
[0263] The precipitate was then filtered over a Buchner funnel.
[0264] The traces of solvent were removed via evaporation under a
reduced pressure of around 20 mmHg.
[0265] The product was in the form of a white solid and was
obtained with a yield of 99%.
Example F
Preparation of 2-fluoro-N-methylpyridinium triflate from
2-chloro-N-methylpyridinium triflate
[0266] In a 50 ml round-bottomed flask topped with a condenser,
2-chloro-N-methylpyridinium triflate (2.7 g, 10 mmol) was dissolved
in 15 ml of acetonitrile.
[0267] Added to this solution was "spray dried" potassium fluoride
(0.64 g, 11 mmol, 1.1 eq.) previously dried under a reduced
pressure of around 20 mmHg at high temperature.
[0268] The whole mixture was refluxed for one hour.
[0269] The potassium chloride was filtered over a Buchner funnel
after cooling the solution.
[0270] The filtrate was concentrated under a reduced pressure of
around 20 mmHg, then was redissolved in 100 ml of
dichloromethane.
[0271] The solid was filtered again and dried under a reduced
pressure of 20 mmHg.
[0272] The product was in the form of a white solid and was
obtained with a yield of 99%.
[0273] The NMR characteristics were the following:
[0274] .sup.1H NMR (300 MHz, DMSO): 4.11 (d, J=4.1 Hz, 3H), 7.86
(m, 1H), 7.98 (dd, J=4.5 Hz, J=8 Hz), 8.62 (m, 1H), 8.80 (m,
1H).
[0275] .sup.13C NMR (75 MHz, DMSO): [0276] Primaries: 41.9 (d,
J=5.3 Hz). [0277] Secondaries: - [0278] Tertiaries: 114.6 (d,
J=20.3 Hz); 124.2 (d, J=3.7 Hz); 144.9 (d, J=7.6 Hz); 151.2 (d,
J=11.6 Hz). [0279] Quaternaries: 157.8 (d, J=276.7 Hz).
Example G
Preparation of 2-fluoro-N-methylpyridinium fluoride from
2-fluoro-N-methylpyridinium triflate
[0280] In a 100 ml round-bottomed flask,
2-fluoro-N-methylpyridinium triflate (10 mmol) was dissolved in a
minimum of acetonitrile (5 ml).
[0281] Added to this mixture was TBAT dissolved in 50 ml of
dichloromethane.
[0282] A white precipitate formed immediately.
[0283] The latter was filtered over a Buchner funnel and washed
with dichloromethane.
[0284] The solid was then dried under a reduced pressure of around
20 mmHg.
Example H
Preparation of 2-fluoro-N-methylpyridinium fluoride from
2-fluoro-N-methylpyridinium triflate
[0285] In a 25 ml round-bottomed flask, 2-fluoro-N-methylpyridinium
tosylate (10 mmol) was dissolved in 10 ml of dichloromethane.
[0286] Added to this mixture was TBAT dissolved in 10 ml of
dichloromethane.
[0287] A white precipitate formed immediately.
[0288] The latter was filtered over a Buchner funnel and washed
with dichloromethane.
[0289] The solid was then to be dried under a reduced pressure of
around 20 mmHg.
[0290] The ion exchange was quantitative regardless of the
method.
[0291] The NMR characteristics were the following:
[0292] .sup.1H NMR (300 MHz, DMSO): 4.11 (d, J=4.1 Hz, 3H), 7.86
(ddd, J=1.2 Hz, J=6.3 Hz, J=7.5 Hz, 1H), 7.99 (ddd, J=1 Hz, J=4.6
Hz, J=8.6 Hz), 8.62 (m, 1H), 8.81 (ddd, J=1.8 Hz, J=4.6 Hz, J=6.3
Hz, 1H).
[0293] .sup.13C NMR (75 MHz, DMSO): [0294] Primaries: 41.6 (d, J=5
Hz). [0295] Secondaries: - [0296] Tertiaries: 114.3 (d, J=20.3 Hz);
123.9 (d, J=3.8 Hz); 144.8 Hz (d, J=7.6 Hz); 150.8 (d, J=11.6 Hz).
[0297] Quaternaries: 158.9 (d, J=271.9 Hz).
Example I
Preparation of N-methyl-2-chloroquinolinium triflate
##STR00010##
[0299] In a 50 ml round-bottomed flask, 2-chloroquinoline (20 mmol)
was dissolved in 30 ml of toluene.
[0300] The mixture was cooled in an ice bath and methyl triflate
(11 eq.) was added.
[0301] The whole mixture was left stirring for 8 hours at room
temperature.
[0302] The white solid that precipitated was then filtered and
washed with toluene.
[0303] It was then dried under a reduced pressure of around 20
mmHg.
[0304] The quinolinium salt was obtained with a yield of 95%.
[0305] The NMR characteristics were the following:
[0306] .sup.1H NMR (CDCl.sub.3, 300 MHz): 0.80 (s, 3H); 7.97 (m,
1H); 8.04 (d, J=8.8 Hz, 1H); 8.22-8.3 (m, 2H); 8.47 (d, J=9.5 Hz,
1H); 8.94 (d, J=8.8 Hz, 1H).
Example J
Preparation of N-methyl-2-fluoroquinolinium triflate
##STR00011##
[0308] The same procedure was used as for obtaining
N-methyl-2-fluoropyridinium triflate from
N-methyl-2-chloropyrdinium triflate, with similar yields.
Example K
Preparation of N-methyl-2-fluoroquinolinium fluoride
##STR00012##
[0310] The same procedure was used as for obtaining
N-methyl-2-fluoropyridinium fluoride from
N-methyl-2-fluoropyridinium triflate, with similar yields.
Example 1
Preparation of 1-fluorodecane
##STR00013##
[0312] In a 5 ml round-bottomed flask, tetrabutylammonium
hydrogendifluoride (560 mg, 2 mmol) was dried under a reduced
pressure of 1 mmHg, at 100.degree. C. for 1/2 hour.
[0313] After cooling, triethylamine (0.14 ml, 1 mmol) was
added.
[0314] The whole mixture was dissolved in chloroform, then
1-decanol (158 mg, 1 mmol) and 1-methyl-2-fluoro-pyridinium
tosylate (560 mg, 2 mmol) were added.
[0315] The mixture was heated under reflux of chloroform for 5
hours.
[0316] It was then hydrolyzed with 2 ml of water and neutralized
with a saturated aqueous solution of sodium
monohydrogencarbonate.
[0317] The extraction was carried out with 4 times 5 ml of
petroleum ether.
[0318] The organic phase was dried over magnesium sulfate, filtered
and concentrated under a reduced pressure of 250 mmHg.
[0319] The residue was purified by chromatography on a silica
column (eluent: petroleum ether).
[0320] After evaporation, the product was then in the form of a
transparent liquid and was obtained with a yield of 56% (m=90
mg).
[0321] The NMR characteristics were the following:
[0322] .sup.1H NMR (CDCl.sub.3, 300 MHz): 0.81 (t, J=8 Hz, 3H);
1.1-1.3 (m, 14H); 1.5-1.7 (m, 2H); 4.37 (dt, J=47.4 Hz, J=6.2 Hz,
2H).
[0323] .sup.13C NMR (CDCl.sub.3, 75 MHz): [0324] Primaries: 14.1.
[0325] Secondaries: 22.7; 25.2; 25.3; 29.3 (d, J=4 Hz); 29.5; 30.4
(d, J=19 Hz); 31.9; 84.3 (d, J=164 Hz). [0326] Tertiaries: - [0327]
Quaternaries: -
Example 2
Preparation of 2-fluorodecane
##STR00014##
[0329] In a 5 ml round-bottomed flask, tetrabutylammonium
hydrogendifluoride (560 mg, 2 mmol) was dried under a reduced
pressure of 1 mmHg, at 100.degree. C. for 1/2 hour.
[0330] After cooling, triethylamine (0.14 ml, 1 mmol) was
added.
[0331] The whole mixture was dissolved in chloroform, then
2-decanol (158 mg, 1 mmol and 1-methyl-2-fluoro-pyridinium tosylate
(560 mg, 2 mmol) were added.
[0332] The mixture was heated under reflux of chloroform for 5
hours.
[0333] It was then hydrolyzed with 2 ml of water and neutralized
with a saturated aqueous solution of sodium
monohydrogencarbonate.
[0334] The extraction was carried out with 4 times 5 ml of
petroleum ether.
[0335] The organic phase was dried over magnesium sulfate, filtered
and concentrated under a reduced pressure of 250 mmHg.
[0336] The residue was purified by chromatography on a silica
column (eluent: petroleum ether).
[0337] The product was then in the form of a transparent liquid and
was obtained with a yield of 43% (m=69 mg).
[0338] The NMR characteristics were the following:
[0339] .sup.1H NMR (CDCl.sub.3, 300 MHz): 0.75-0.85 (m, 6H);
1.1-1.3 (m, 14H); 4.37 (m, 1H).
[0340] .sup.13C NMR (CDCl.sub.3, 75 MHz): [0341] Primaries: 14.1;
21.0 (d, J=23 Hz). [0342] Secondaries: 22.3; 22.6; 25.1 (d, J=5
Hz); 29.2; 29.5 (d, J=2 Hz); 31.9; 37.0 (d, J=21 Hz). [0343]
Tertiaries: 91.1 (d, J=164 Hz).
Quaternaries: -
Example 3
Preparation of 2-fluoro-1,2-diphenylethanone
##STR00015##
[0345] In a 5 ml round-bottomed flask, tetrabutylammonium
hydrogendifluoride (280 mg, 1 mmol) was dried under a reduced
pressure of 1 mmHg at 100.degree. C. for 1/2 hour.
[0346] After cooling, triethylamine (0.07 ml, 1 mmol) was
added.
[0347] The whole mixture was dissolved in chloroform, then benzoin
(106 mg, 0.5 mmol) and 1-methyl-2-fluoro-pyridinium tosylate (280
mg, 1 mmol) were added.
[0348] The mixture was heated under reflux of chloroform
overnight.
[0349] It was then hydrolyzed with 2 ml of water and neutralized
with a saturated aqueous solution of sodium
monohydrogencarbonate.
[0350] The extraction was carried out with 4 times 5 ml of ethyl
ether.
[0351] The organic phase was dried over magnesium sulfate, filtered
and concentrated under a reduced pressure of 20 mmHg.
[0352] The residue was purified by chromatography on a silica
column (eluent: petroleum ether/dichloromethane:1/1;
R.sub.f=0.25).
[0353] The product was then in the form of a white solid (melting
point: 53.degree. C.) and was obtained with a yield of 87% (m=93
mg).
[0354] The NMR characteristics were the following:
[0355] .sup.1H NMR (CDCl.sub.3, 300 MHz): 6.52 (d, J=48.7 Hz, 1H);
7.3-7.6 (m, 8H); 7.9-8.0 (m, 2H).
[0356] .sup.13C NMR (CDCl.sub.3, 75 MHz): [0357] Primaries: -
[0358] Secondaries: - [0359] Tertiaries: 94.0 (d, J=186 Hz); 127.3
(d, J=6 Hz); 128.7; 129.1; 129.1; 129.6 (d, J=3 Hz) 133.8. [0360]
Quaternaries: 134.1; 134.3 (d, J=20 Hz); 194.3 (d, J=21 Hz).
Example 4
Preparation of ethyl fluorophenylacetate
##STR00016##
[0362] In a 5 ml round-bottomed flask, tetrabutylammonium
hydrogendifluoride (280 mg, 1 mmol) was dried under a reduced
pressure of 1 mmHg at 100.degree. C. for 1/2 hour.
[0363] After cooling, triethylamine (0.07 ml, 1 mmol) was
added.
[0364] The whole mixture was dissolved in chloroform (1 ml), then
ethyl mandelate (90 mg, 0.5 mmol) and 1-methyl-2-fluoropyridinium
tosylate (280 mg, 1 mmol) were added.
[0365] The mixture was heated under a reflux of chloroform for
three hours.
[0366] It was then hydrolyzed with 5 ml of water.
[0367] The extraction was carried out with 3 times 5 ml of ethyl
ether.
[0368] The organic phase was dried over magnesium sulfate, filtered
and concentrated under a reduced pressure of around 20 mmHg.
[0369] The residue was purified by chromatography on a silica
column (eluent: petroleum ether/dichloromethane:1/1).
[0370] The product was then in the form of a colorless liquid and
was obtained with a yield of 56% (m=51 mg).
[0371] The NMR characteristics were the following:
[0372] .sup.1H NMR (CDCl.sub.3 300 MHz): 1.29 (t, J=7.3 Hz; 3H)
4.25 (q, J=7.3 Hz; 2H); 5.76 (d, J=48.2 Hz; 1H); 7.10-7.48 (m,
5H).
Example 5
Preparation of isopropyl fluorophenylacetate
##STR00017##
[0374] In a 5 ml round-bottomed flask, tetrabutylammonium
hydrogendifluoride (280 mg, 1 mmol) was dried under a reduced
pressure of 1 mmHg at 100.degree. C. for 1/2 hour.
[0375] After cooling, triethylamine (0.07 ml, 1 mmol) was
added.
[0376] The whole mixture was dissolved in chloroform (1 ml), then
isopropyl mandelate (90 mg, 0.5 mmol) and
1-methyl-2-fluoropyridinium tosylate (280 mg, 1 mmol) were
added.
[0377] The mixture was heated under a reflux of chloroform for
three hours.
[0378] It was then hydrolyzed with 5 ml of water.
[0379] The extraction was carried out with 3 times 5 ml of ethyl
ether.
[0380] The organic phase was dried over magnesium sulfate, filtered
and concentrated under a reduced pressure of around 20 mmHg.
[0381] The residue was purified by chromatography on a silica
column (eluent: petroleum ether/dichloromethane:1/1).
[0382] The product was then in the form of a colorless liquid and
was obtained with a yield of 63% (m=62 mg).
[0383] The NMR characteristics were the following:
[0384] .sup.1H NMR (CDCl.sub.3, 300 MHz): 1.20 (t, d=6.3 Hz; 3H);
1.30 (t, d=6.3 Hz; 3H); 5.12 (spt, J=6.3 Hz; 1H); 5.76 (d, J=48.0
Hz; 1H) 7.10-7.48 (m, 5H).
[0385] .sup.13C NMR (CDCl.sub.3, 75 MHz) [0386] Primaries: 21.5;
21.7. [0387] Secondaries: - [0388] Tertiaries: 69.7; 89.4 (d, J=185
Hz); 126.6; 127.9; 128.7. [0389] Quaternaries: 134.6 (d, J=38 Hz);
168.1 (d, J=27 Hz).
Example 6
Preparation of 1-difluoromethyl-4-methoxybenzene
##STR00018##
[0391] In a 25 ml round-bottomed flask tetrabutylammonium
hydrogendifluoride monohydrate (3 g; 10 mmol; 3.3 eq.) was
introduced.
[0392] The latter was heated at 100.degree. C. in an oil bath under
a reduced pressure of 1 mmHg for one hour.
[0393] After cooling under argon, 1-methyl-2-fluoropyridinium
tosylate (2.8 g; 10 mmol; 3.3 eq.) was introduced followed by
anisaldehyde (408 mg; 3 mmol) and triethylamine (1.4 ml; 10 mmol;
3.3 eq.).
[0394] After stirring for 5 minutes, the mixture was then brought
to 80.degree. C. and became completely homogeneous.
[0395] After 5 hours, the mixture was hydrolyzed with water (5 ml),
and neutralized with a saturated solution of sodium
hydrogencarbonate (10 ml).
[0396] The aqueous solution was then extracted with diethyl ether
(3 times 20 ml).
[0397] The organic phase was dried over magnesium sulfate.
[0398] After filtration, the solvent was evaporated under a reduced
pressure of around 20 mmHg.
[0399] The black liquid residue had, in thin-layer chromatography,
two spots at respective Rf values 0.27 and 0.71 (petroleum
ether/dichloromethane 1/1) or 0.08 and 0.41 (petroleum
ether/dichloromethane 3/1).
[0400] Chromatography is carried out on a silica column by eluting
with a petroleum ether/dichloromethane gradient of 3/1 to 1/1.
[0401] The 1-difluoromethyl-4-methoxybenzene was in the form of a
slightly yellow oil (278 mg; 1.76 mmol; 59%).
[0402] The anisaldehyde recovered was a white solid (100 mg; 0.73
mmol; 24%).
[0403] The NMR characteristics were the following:
[0404] .sup.1H NMR (CDCl.sub.3, 300 MHz): 3.85 (s, 3H); 6.62 (t,
J=56.8 Hz, 1H); 6.96 (d, J=8.9 Hz, 2H); 7.45 (d, J=8.9 Hz, 2H).
[0405] .sup.13C NMR (CDCl.sub.3, 75 MHz): [0406] Primaries: 55.34.
[0407] Secondaries: - [0408] Tertiaries: 114.0; 114.9 (t, J=237
Hz); 127.1 (t, J=6 Hz). [0409] Quaternaries: 126.5 (t, J=23 Hz),
161.4.
Example 7
Preparation of 1,4-bis(trifluoromethyl)benzene
##STR00019##
[0411] In a 5 ml round-bottomed flask, tetrabutylammonium
hydrogendifluoride (750 mg, 2.5 mmol) was dried under a reduced
pressure of 1 mmHg at 100.degree. C. for 1 hour.
[0412] After cooling, triethylamine (0.35 ml, 2.5 mmol),
1-methyl-2-fluoropyridinium tosylate (700 mg, 2.5 mmol), then
terephthaldehyde (36 mg, 0.25 mmol) were added.
[0413] The whole mixture was heated at 80.degree. C. for 6
hours.
[0414] It was then hydrolyzed with 3 ml of water and neutralized
with a saturated aqueous solution of sodium monohydrogencarbonate
(3 ml).
[0415] The extraction was carried out with 3 times 5 ml of ethyl
ether.
[0416] The organic phase was dried over magnesium sulfate, filtered
and concentrated under a reduced pressure of around 20 mmHg.
[0417] The residue was purified by chromatography on a silica
column (eluent: gradient of dichloromethane in petroleum
ether).
[0418] The product was then in the form of a colorless liquid and
was obtained with a yield of 30% (m=13 mg).
[0419] 4-Difluoromethylbenzaldehyde was isolated with a yield of
20% (8 mg).
[0420] The chromatography results were:
[0421] Eluent: petroleum ether/dichloromethane:1/1.
[0422] Developer: UV.
[0423] Retardation factor: Rf.sub.1=0.8; and [0424]
Rf.sub.2=0.27.
[0425] The NMR characteristics were the following:
[0426] .sup.1H NMR (CDCl.sub.3, 300 MHz): 6.70 (t, J=56.5 Hz, 2H);
7.62 (s, 4H).
[0427] .sup.13C NMR (CDCl.sub.3, 75 MHz): [0428] Primaries: -
[0429] Secondaries: - [0430] Tertiaries: 114.0 (t, J=239 Hz); 126.0
(t, J=6 Hz). [0431] Quaternaries: 136.7 (t, J=22 Hz).
4-Difluoromethylbenzaldehyde
[0432] .sup.1H NMR (CDCl.sub.3 300 MHz): 6.71 (t, J=55.9 Hz, 1H);
7.70 (d, J=7.9 Hz, 2H); 7.99 (d, J=7.9 Hz, 2H); 10.09 (s, 1H).
Example 8
Preparation of 10,10-difluorophenanthren-9-one
##STR00020##
[0434] In a 10 ml round-bottomed flask, tetrabutylammonium
hydrogendifluoride (2.8 g, 10 mmol) was dried under a reduced
pressure of 1 mmHg at 100.degree. C. for 1 hour.
[0435] After cooling, triethylamine (0.7 ml, 10 mmol) and
1-methyl-2-fluoropyridinium tosylate (2.8 g, 10 mmol) were
added.
[0436] The whole mixture was left stirring magnetically until a
homogeneous solution was obtained (slight heating may be
necessary).
[0437] Phenanthrene-9,10-dione (208 mg, 1 mmol) was then added and
the mixture was heated at 80.degree. C. overnight.
[0438] It was then hydrolyzed with 3 ml of water and neutralized
with a saturated aqueous solution of sodium
monohydrogencarbonate.
[0439] The extraction was carried out with 4 times 10 ml of ether
ethyl.
[0440] The organic phase was dried over magnesium sulfate, filtered
and concentrated under a reduced pressure of around 20 mmHg.
[0441] The residue was purified by chromatography on a silica
column (eluent: petroleum ether/dichloromethane:1/1; Rf=0.3).
[0442] The product was then in the form of a white solid (melting
point: 90.degree. C.) and was obtained with a yield of 58% (m=124
mg).
[0443] The NMR characteristics were the following:
[0444] .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.48 (m, 2H); 7.61 (tq,
J=1.3 Hz, J=7.5 Hz, 1H); 7.74 (ddd, J=1.5 Hz J=7.5 Hz J=8 Hz, 1H);
7.87 (dd, J=1 Hz, J=7.7 Hz, 1H); 7.94 (m, 2H); 8.09 (ddd, J=0.5 Hz,
J=1.5 Hz, J=7.7 Hz, 1H).
[0445] .sup.13C NMR (CDCl.sub.3, 75 MHz): [0446] Primaries: -
[0447] Secondaries: - [0448] Tertiaries: 123.7; 124.4; 127.3 (t,
J=5 Hz); 128.8 (t, J=1 Hz); 129.3; 129.6 (t, J=1 Hz); 132.4 (t, J=2
Hz); 136.2. [0449] Quaternaries: 108.0 (t, J=245 Hz); 127.7 (t, J=2
Hz); 130.2 (t, J=23 Hz); 131.7 (t, J=6 Hz); 136.1 (t, J=2 Hz);
186.9 (t, J=26 Hz).
* * * * *